Process for making optically active naphtho[1,2-b]thiazepin-4(5H)-ones

ABSTRACT

A process for preparing optically active naphtho[1.2-b][1,4]thiazepin-4(5H)-ones comprising resolution of rac-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid and converting the optically active acids so obtained into final products is described. The end product naphtho[1,2-b][1,4]thiazepin-4(5H)-ones have activity as calcium channel blockers and accordingly are useful as agents for lowering blood pressure, and as agents for treating ischemia.

This is a division of application Ser. No. 07/373,741, filed Jun. 29,1989, now U.S. Pat. No. 4,996,325, which is a division of applicationSer. No. 07/192,252, filed May 10, 1988 now U.S. Pat. No. 4,864,058.

BRIEF SUMMARY OF THE INVENTION

The invention relates to a process for the preparation of opticallyactive naphtho[1,2-b][1,4]thiazepin-4(5H)-ones which comprises resolvingthe racemic acid,rac-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid of the formula ##STR1## into its enantiomers and using saidoptically pure enantiomers for conversion into optically activenaphtho[1,2-b][1,4]thiazepin-4(5H)-ones.

More specifically, the process of the invention comprises:

(a) treatment of a solution of the racemic acid,rac-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid with (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolineto form diastereomeric salts (+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline hydratewhich crystallizes and(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate, which remains in solution;

(b) separating the crystalline diastereomeric salt of step (a) byfiltration, and purifying by recrystallization;

(c) obtaining the optically pure enantiomeric acid(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid by treatment of the optically pure salt from step (b) with aninorganic acid;

(d) recovering the resolving agent(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline;

(e) concentrating the mother liquor from step (b) and treating theresidue with an inorganic acid; and isolating crude(-)-β-[(2-amino-1-naphthalenyl)thio]-β-hydroxy-4-methoxybenzenepropanoicacid by extraction;

(f) treating the crude acid from step (e) with(-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline separatingthe resulting crystalline salt by filtration and further purifying byrecrystallization;

(g) obtaining the optically pure enantiomeric acid(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid by treating the optically pure, diastereomeric salt resulting fromstep (f),(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octanhydroisoquanolinehydrate, with an inorganic acid.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a process for preparing optically activenaphtho[1,2-b][1,4]thiazepin-4(5H)-ones. The process involves resolutionof the racemic acid,rac-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid of the formula ##STR2## into its enantiomers(+)-β-([2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid and(-)-β-([2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid of the formulas ##STR3## The process specifically comprises: (a)treatment of a solution of the racemic acidrac-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid with (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolineto form diastereomeric salts (+)-β-([2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline hydratewhich crystallizes and(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate, which remains in solution;

(b) separating the crystalline diastereomeric salt of step (a) byfiltration and purifying by recrystallization;

(c) obtaining the enantiomeric acid(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid by the treatment of its corresponding optically active salt with aninorganic acid; and

(d) recovering the resolving agent(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline.

(e) concentrating the mother liquor from step (b) and isolating crude(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid by extraction;

(f) treating the crude(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid isolated from step (e) with(-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline; and

(g) obtaining the enantiomeric acid(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid by treating the salt resulting from step (f)(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid(-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline hydratewith inorganic acid.

The resolutions of the compound of formula II ##STR4## which is arac-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid into compounds of formulas ##STR5## can be carried out with theresolving agent of formula III ##STR6## which is(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline bydissolving the two just mentioned compounds of formula II and formulaIII in absolute ethanol heated on a steam bath. The resulting solutionmay optically be treated with seed crystals of the salt mentioned justbelow. The resulting salt(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate crystallizes and can be separated by filtration and purified byrecrystallization. The compound of formula II is disclosed in U.S. Pat.No. 4,652,561.

The just above mentioned salt can be decomposed by treatment with aninorganic acid such as sulfuric acid or more preferably hydrochloricacid to obtain optically pure enantiomeric acid(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid of formula II' ##STR7##

The resolving agent,(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline is knownas set forth in Helvetic Chimica Acta, Volume 39, fasciculus II (1956)Number 49--49 pages 429-440 which is incorporated herein by reference.

U.S. Pat. No. 4,652,561 is also incorporated herein be reference.

The resolving agent,(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline may berecovered by making basic the above described solution which was treatedwith inorganic acid. The base used may be ammonium hydroxide. Theresulting suspension is extracted with an organic solvent such aschloroform or more preferably methylene chloride, and the abovementioned resolving agent is recovered by usual separatory techniques.

The compound of formula II" ##STR8## which is(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid can be obtained by combining the mother liquors obtained in theseparation of the above mentioned diastereomeric salt(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate. These combined mother liquors are concentrated to dryness, theresidue is decomposed with an inorganic acid such as sulfuric acid, ormore preferably hydrochloric acid. The resulting suspension is extractedwith an organic solvent such as methylene chloride or more preferablyethyl acetate.

Removal of this organic solvent gives crude(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid which is further purified by reaction with the resolving agent(-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline inabsolute ethanol heated on a steam bath. The resulting solution mayoptionally be seeded with a few crystals of the salt mentioned justbelow. The resulting diastereomeric salt(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid(-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline isseparated by filtration and further purified by recrystallization.

In this manner, the just above mentioned salt may be obtained insubstantially optically pure form. Succeeding compounds in the synthesismay also be obtained in substantially optically pure form by the processdisclosed herein.

Recovery of(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid of formula II" ##STR9## is achieved by decomposing the just abovementioned diastereomeric salt with an inorganic acid such as sulfuricacid, or more preferably hydrochloric acid. The resulting suspension isextracted with an organic solvent such as methylene chloride or morepreferably ethyl acetate. The just above mentioned acid is thenrecovered by usual separatory techniques.

Recovery of(-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline can beachieved by making basic the solution which was acidified to obtain the(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid. The base used is ammonium hydroxide. The resulting suspension isextracted with an organic solvent such as chloroform or more preferablymethylene chloride. The(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline may beobtained from the extracts by usual separatory techniques.

The optically pureβ-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacids obtained may be used to prepare optically purenaphtho[1,2-b][1,4]thiazepin-4(5H)-ones.Naphtho[1,2-b][1,4]thiazepin-4(5H)-ones have activity as calcium channelblockers and accordingly, are useful as agents for lowering bloodpressure, and as agents for treating ischemia.

The optically pure just above mentioned acids may be converted to theend product naphtho[1,2-b][1,4]thiazepin-4(5H)-ones as follows.

A compounds of formula II' or II" can be cyclized respectively to thecompounds of formula ##STR10## by reaction in the presence of acatalytic amount of an acid such as p-toluenesulfonic acid in anaromatic solvent such as, benzene, xylene or more preferably toluene, atreflux for a period of about 12 to about 72 hours. Isolation ofcompounds of formula IV' or IV" can be by conventional means such asrecrystallization.

It will be understood that formula ##STR11## encompasses compounds offormulas IV' and IV"

A compound of formula IV can be converted to a compound of formula##STR12## by reaction with the compound of the formula

    ClCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                      V

The reaction is carried out by reacting an alkali metal salt of acompound of formula IV, such as the sodium or more preferably potassiumsalt thereof with an aminoalkyl halide of formula V, preferably thechloride thereof, in a polar organic solvent such as, methyl acetate, ormore preferably ethyl acetate, at about 40° to about 80°, or at thereflux temperature of the solvent employed, which in the case of ethylacetate is 77°, for a period of about 1 hour to about 17 hours. Thereaction is carried out in the presence of a base, such as, potassiumhydroxide in acetone or more preferably potassium carbonate in acetoneor in a lower alkyl acetate. Separation of the compound of formula Iacan be by conventional means such as crystallization.

Specifically, a compound of formula Ia, can be acylated by reaction withacetic anhydride, or acetyl chloride optionally in the presence of abase such as, pyridine, triethylamine, or dimethylaniline at roomtemperature or up to about 115°.

Alternatively, an alkali metal salt, such as a sodium salt, of acompound of formula Ia may be reacted with an alkylating agent such asdialkyl sulfate, more particularly, dimethyl sulfate in an aromaticsolvent such as toluene or more preferably benzene, at about refluxtemperature for about 10 minutes to about 2 hours.

Also, a compound of formula Ia may be reacted with an alkyl halo formatesuch as ethyl chloroformate in a basic solvent such as pyridine at aboutice bath temperatures.

Moreover, a compound of formula Ia may be reacted with an alkoxyalkanoyl halide such as, methoxyacetyl chloride in a basic solvent suchas pyridine at about ice bath temperatures.

Furthermore, a compound of formula Ia may be reacted with acycloalkylcarboxylic acid halide, such as, cyclopropane carboxylic acidchloride in a basic solvent such as pyridine at about ice bathtemperatures.

All of the just above mentioned reactions of compounds of formula Iayield compounds of formula Ib ##STR13## wherein R₂ is lower alkanoyloxy,lower cyclocarbonyloxy; ##STR14## wherein m is 1 to 2.

Compounds of formulas Ia and Ib are encompassed by formula I ##STR15##wherein R₂ is hydroxy, lower alkanoyloxy, lower cyclocarbonyloxy;##STR16## wherein m is 1 to 2.

Processes for converting a compound of formula Ia to a compound offormula I are set forth in more detail in U.S. Pat. No. 4,652,561.

Compounds of formula I, as described in U.S. Pat. No. 4,652,561, arecalcium channel blockers useful as agents for lowering blood pressureand treating ischemia.

It can be seen that the difference between the process of the inventionand the process set forth in U.S. Pat. No. 4,652,561, is that in theprocess of the invention, the resolution into optically activeenantiomers occurs at an early stage giving compounds of the formulas##STR17## whereas in U.S. Pat. No. 4,652,561 separation at a late stageyields, optically active enantiomers of the formulas ##STR18##

An advantage to the present process is that resolution into opticallyactive enantiomers at the earlier stage as the just above mentionedacids of formulas II' and II" means that the process can be carried outusing smaller amounts of reactants with a resulting saving in expense.

A further advantage of the process of the invention is the recovery ofresolving agent. Recovering of the resolving agent is economical andfurther avoids pollution of the environment with by-products of theprocess.

The examples which follow, further illustrate the invention. Alltemperatures are in degrees Celsius unless otherwise mentioned.

EXAMPLE 1 Resolution ofrac-β-[(2-Amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicAcid

A mixture of 7.38 g (0.0199 mol) of(±)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid and 4.84 g (0.0199 mol) of(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline in 400 mLof ethanol (absolute) was heated on the steam bath until clear solutionobtained, then seeded with a few crystals of(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate and allowed to crystallize at room temperature overnight. Thecrystals were separated by filtration and dried to yield 6.3 g of salt,mp 145°-147° (decomposes, shrinks at 140°), [α]_(D) ²⁵ +290° (C 0.5,MeOH-heat the sample to dissolve). One recrystallization from methanol(390 mL) as above yielded 5.75 g (91.2%) of pure(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate, mp 142°-144° (decomposes, shrinks at 140°), [α]_(D) ²⁵ +288.71°(C 0.195, MeOH).

C₂₀ H₁₉ NO₄ S.C₁₆ H₂₁ NO.H₂ O(630.80)

Calcd: C, 68.55; H, 6.71; N, 4.44

Found: C, 68,90; H, 6.72; N, 4.38

EXAMPLE 2(+)-β-[(2-Amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicAcid

(30)-β-[(2-Amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline, 5.0 g(0.0079 mol) was decomposed in 60 mL 1N HCl. The resulting suspensionwas extracted with ethyl acetate (3×100 mL). The combined ethyl acetatesolutions were dried (MgSO₄) and removal of the solvent gave 3.25 g ofcrude acid of the title. Recrystallization from CHCl₃ (10 mL) overnightafforded 2.81 g (96.2%) of(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid, mp 143°-145°. The analytical sample was recrystallized frombenzene, mp 143°-145°, [α]_(D) ²⁵ +269.51° (C 0.52, MeOH).

C₂₀ H₁₉ NO₄ S(369.36)

Calcd: C, 65.02; H, 5.18; N, 3.79

Found: C, 65.00; H, 5.20; N, 3.75

EXAMPLE 3 Recovery of(+)-1-(p-Hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline

The 1N HCl solution obtained in the isolation of (+)-acid in Example 2was made basic with concentrated NH₄ OH and the resulting suspension wasextracted with methylene chloride (2×75 mL). The combined CH₂ Cl₂solutions were dried (MgSO₄) and removal of the solvent gave 1.5 g(78.1%) of(+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, mp156°-158° (no mixture mp depression with an authentic sample), [α]_(D)²⁵ +165° (C 1.0, MeOH).

EXAMPLE 4(-)-β-[(2-Amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicAcid

The combined mother liquors obtained in the separation of(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate were concentrated to dryness. The residue was decomposed with 75mL of 1N HCl and the resulting suspension was extracted with ethylacetate (3×100 mL). The combined ethyl acetate solutions were dried(MgSO₄) and removal of the solvent gave 3.91 g of crude(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid.

A mixture of 3.91 g (0.011 mol) of crude(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid, 2.57 g (0.011 mol) of(-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline in 110 mLof ethanol (absolute) was heated on the steam bath until a clearsolution was obtained, then seeded with a few crystals of(-)-β-[(2-amino-1-naphthalenyl)thio-α-hydroxy-4-methoxybenzenepropanoicacid (-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate and allowed to crystallize at room temperature overnight. Thecrystals were separated by filtration and dried to yield 5.91 g of salt,mp 142°-144° (decomposition, shrinks at 140°). One recrystallizationfrom ethanol (365 mL) overnight yielded 5.4 g (85.7%) of pure(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate, mp 145°-147° (decomposition, shrinks at 140°), [α]_(D) ²⁵-285.74° (C 0.25, MeOH; heat the sample to dissolve).

C₂₀ H₁₉ NO₄ S.C₁₆ H₂₁ NO.H₂ O(630.80)

Calcd: C, 68.55; H, 6.71; N, 4.44

Found: C, 68.98; H, 6.46; N, 4.37

EXAMPLE 5 Recovery of(+)-1-(p-Hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline

The 1N HCl solution obtained in the isolation of(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4methoxybenzenepropanoicacid was made basic with concentrated NH₄ OH and the resultingsuspension was extracted with methylene chloride (3×75 mL). The combinedCH₂ Cl₂ solutions were dried (MgSO₄) and removal of the solvent gave2.36 g of (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline,mp 154°-156° (no mixture mp depression with authentic sample), [α]_(D)²⁵ +162° (C 1.0, MeOH).

EXAMPLE 6(-)-β-[(2-Amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicAcid

(-)-β-[(2-Amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid (-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, 4.9g (0.0077 mol) was decomposed in 60 mL of 1N HCl. The resultingsuspension was extracted with ethyl acetate (3×100 mL). The combinedethyl acetate solutions were dried (MgSO₄) and removal of the solventgave 2.9 g of crude(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid. Recrystallization rom CHCl₃ (10 mL) overnight afforded 2.37 g(82.8%) of (-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid, mp 142°-144°. Theanalytical sample was recrystallized from benzene, mp 143°-145°, [α]_(D)²⁵ -268.32° (C 0.476, MeOH).

C₂₀ H₁₉ NO₄ S(369.36)

Calcd: C, 65.02; H, 5.18; N, 3.79

Found: C, 64.89; H, 5.20; N, 3.77

EXAMPLE 7 Recovery of(-)-1-(p-Hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline

The 1N HCl solution obtained in the isolation of(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid was made basic with concentrated NH₄ OH and the resultingsuspension was extracted with methylene chloride (2×100 mL). Thecombined CH₂ Cl₂ solutions were dried (MgSO₄) and removal of the solventgave 1.6 g (84.6%) of(-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, mp156°-158° (no mix mp depression with authentic sample), [α]_(D) ²⁵ -162°(C 1.0 MeOH).

EXAMPLE 8 [2S-(2β,3β)]-2,3-Dihydro-3-hydroxy-2-(4-methoxyphenyl)-naphtho[1,2-b][1,4]thiazepin-4(5H)-one

A mixture of 1.0 g (0.0027 mol) of(+)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid and 0.1 g of p-toluensulfonic acid in 50 ml of xylene was stirredand heated at reflux for 1.5 hours using a Dean-Stark water trap. Thereaction mixture wax cooled and the crystals were collected to afford0.8 g (90%) of [2S-(2β,3β)]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]thiazepin-4(5H)-one, mp 240°-241°, [α]_(D) ²⁵ +24.65°(C 0.495, acetone).

C₂₀ H₁₇ NO₃ S(351.34)

Calcd: C, 68.37; H, 4.88; N, 3.99

Found: C, 68.42; H, 4.80; N, 3.92

EXAMPLE 9(+)-cis-2,3-Dihydro-3-hydroxy-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)naptho[1,2-b][1,4thiazepin-4(5H)-one

A mixture of 0.5 g (0.0014 mol) of[2S-(2β,3β)]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]-thiazepin-4(5H)-one,0.23 g (0.0017 mol) of powdered potassium carbonate and 0.2 g (0.00158mol) of 2-dimethylaminoethyl chloride in 30 ml of ethyl acetate wasstirred and heated at reflux for 2 hours, then three times an additional50 mg of 2-dimethylaminoethyl chloride was added at 2 hour intervals.The mixture was heated at reflux for a total of 12 hours, then cooled toroom temperature, diluted with ethyl acetate and washed with brine. Theethyl acetate solution was dried (MgSO₄) and removal of the solvent gave0.6 g of crude product, which on crystallization from ethyl acetate gave0.5 g (85%) of(+)-cis-2,3-dihydro-3-hydroxy-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]thiazepin-4(5H)-one,mp 170°-172°, [α]_(D) ²⁵ +40.0° (C 1.0, MeOH).

EXAMPLE[2R-(2α,3α)]-2,3-Dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]thiazepin-4(5H)-one

A mixture of 1.0 g (0.0027 mol) of(-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoicacid and 0.1 g of p-toluenesulfonic acid in 50 ml of xylene was stirredand heated at reflux for 1.5 hours using a Dean-Stark water strap. Aftercooling the crystals were collected to provide 0.80 g (80%) of[2R-(2α,3α)]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]thiazepin-4(5H)-one,mp 238°-239°, [α]_(D) ²⁵ -22.97° (C 0.51, acetone).

C₂₀ H₁₇ NO₃ S(351.34)

Calcd: C, 68.37; H, 4.88; N, 3.99

Found: C, 68.49; H, 4.68; H, 3.96

We claim: 1.(+)-.beta.-[(2-amino-1-naphthalenyl)-thio]-α-hydroxy-4-methoxybenzenepropanoicacid (+)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate. 2.(-)-.beta.-[(2-amino-1-naphthalenyl)-thio-]α-hydroxy-4-methoxybenzenepropanoicacid (-)-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinehydrate.